Malignant melanoma represents one of the most aggressive malignancies but outcome is highly variable with early tumor lesions having an excellent prognosis following resection. We review here the data on identification of genes involved in the progression of melanoma as a result of expression array studies, genomic profiling, and genetic models. We focus on the role of tumor suppressors involved in cell cycle function, DNA repair, and genome maintenance. Highlighted are the roles of loss of p16 in promoting neoplasia in cooperation with deregulated MAPK signaling, and the role of loss of the RASSF1A protein in promoting chromosomal instability. The interactions between point mutation in growth signaling molecules and epigenetic changes in genes involved in DNA repair and cell division are discussed.